Compounds for treatment of pain

ABSTRACT

The aspects of the disclosed embodiments are directed to novel compounds, formulations containing said compounds or pharmaceutically acceptable salts thereof which are suitable for administration to a patient.

FIELD

The aspects of the disclosed embodiments are directed to novelcompounds, formulations containing said compounds or pharmaceuticallyacceptable salts thereof which are suitable for administration to apatient.

BACKGROUND

This disclosure is directed to quaternary oxycodone, oxymorphone,hydrocodone and hydromorphone ammonium compounds described in generalFormula I and to compositions and uses of said compounds for treatingpain associated with a variety of chronic human disorders including forexample neuropathic pain and pain associated with cancer, surgeries orinjuries.

The compounds of the disclosure may be generically categorized withinthe class of compounds known as opioids. It is well known that opioiddrugs target three types of endogenous opioid receptors (i.e., mu, deltaand kappa receptors) in biological systems. Most opioids, such asmorphine, are mu opioid agonists that are often used as analgesics forthe treatment of severe pain due to their activation of mu opioidreceptors in the brain and central nervous system (CNS). Opioidreceptors are, however, not limited to the CNS, and have been found inother tissues throughout the body. A number of side effects of opioiddrugs may be caused by activation of these peripheral receptorsincluding nausea, vomiting and inhibition of normal propulsivegastrointestinal function resulting in side effects such as, forexample, constipation, drowsiness, respiratory depression, changes inmood, and mental clouding without a resulting loss of consciousness.Thus, it is widely recognized that opioid treatment induced constipationis sometimes even more difficult to treat than the underlying pain.Towards this end, several ameliorating strategies have been developedwhich include, for example, the administration of opioid receptorantagonist such as for example, Naltrexon to patients for reversingopioid induced constipation. However, since central acting opioidreceptor antagonists also reverse analgesia and precipitate opioidwithdrawal symptoms, non CNS penetrant quaternary ammonium derivativesof opioid antagonist such as for example, Methyl Naltrexone have beendeveloped and these derivatives have been shown to reverse peripheralside effects of opioids without inducing CNS mediated withdrawalsymptoms or reversing analgesia. However, since use of opioidantagonists targets the amelioration of already manifested side effects,these treatment regimens add cost and burden to the treatment of pain.Accordingly there is a need for developing opioid derivatives that wouldexhibit reduced peripheral side-effects while maintaining centralanalgesic properties.

Moreover, prescription opioid use is also the subject of extensive“substance abuse” which is increasing and exacts a high toll onpatients, physicians, and society. Nonmedical users of prescription painrelievers quadrupled from 1990 to 2000, with abuse of oxycodone andhydrocodone products particularly common. Extracting a societal toll,this prescription drug abuse is associated with higher rates ofcomorbidities and drug-related mortality.

Chronic pain and prescription opioid abuse are both highly prevalent.Chronic pain affects approximately 50 million Americans each year, andan additional 48 million Americans 12 years or older have usedprescription drugs for nonmedical reasons in their lifetimes. Among themost potent analgesics available, opioids have a recognized role in thetreatment of cancer- and non-cancer-related chronic pain conditions. Yetmany physicians, concerned that their patients will become addicted, arereluctant to prescribe these agents, contributing to the widespreadundertreatment of chronic pain.

One strategy for reducing the potential for abuse is development oftamper resistant opioid formulations designed to create barriers tomanipulations of prescription drug formulations. Additionally, opioidformulations incorporating pharmacological strategies have also beendesigned to deter or resist misuse and abuse by making it difficult toachieve euphoria through opioid use. As pharmacologically proactivetools, these formulations use either pharmacodynamic or physicalmechanisms to make opioids unattractive to individuals who abuse them,as well as present barriers to unintentional or deliberate misuse. Suchformulations are currently available and have had mixed epidemiologicalresults. New compounds and formulations that obviate the limitations ofexisting therapeutics are thus needed.

Pharmaceutical strategies have been developed as eitheragonist-antagonist or agonist-additional active ingredient combinations.Agonist-antagonist formulations can be considered pharmacodynamicstrategies because they act to reduce reward at the receptor level. Anexample of such a strategy is Embeda™ (Pfizer™), which combines morphinewith an antagonist such as naltrexone. If this formulation is ingestednormally, the naltrexone remains latent; if it is crushed, thenaltrexone is released and reduces the effects of the morphine Otheragonist-antagonist combinations include Talwin™ containing pentazocinehydrochloride and naloxone hydrochloride equivalent; Valoron™, acombination of tilidine and naloxone; and Terngesic, a combination ofbuprenorphine and naloxone. These strategies cause, in some instances,opioid withdrawal symptoms.

Opioids with a reduced side effect and abuse potential are one of themost important unmet needs in the management of chronic pain and helpphysicians to better balance optimal analgesia with reduced risk ofhaving to treat either opioid induced side effects or worry aboutprescription misuse and abuse.

Compounds of the present disclosure combine agonist/antagonist activityat opioid receptors in a single molecular entity and exploit (asprinciple of their pharmacological action) relative drugdistribution/partitioning differences between agonist and quaternaryammonium antagonist in peripheral and central nervous systemcompartments, thereby reducing peripheral side effects associated withopioid receptor agonist use (such asGI effects, or respiratorydepression and pruritis). In addition, by controlling the delivery of acentrally acting analgesic opioid through the rate of enzymaticconversion of a peripheral quaternary ammonium opioid antagonist,compounds of the present invention are abuse-resistant while maintaininganalgesic properties of the parent opioid.

The invention relates to a compound of Formula I:

wherein R¹ is CHR⁴O(C═O)OR⁵, CHR⁴O(C═O)R⁶, CHR⁴O(C═O)NR⁶R⁷,CHR⁴O(C═O)CHR⁸NR⁶R⁷, CHR⁴O(C═O)CHR⁸NH(COCHR⁸NH)_(n)H, CHR⁴R⁹,CHR⁴O(C═O)CR⁵R⁶OR⁷, CHR⁴O(C═O)O(CH₂)_(n)NR⁵R⁶,CHR⁴O(C═O)O(CH₂)_(n)CO₂R⁵, CHR⁴O(C═O)(CH₂)_(n)NR⁵R⁶,CHR⁴O(C═O)(CH₂)_(n)CO₂R⁵,

R² is H, OH, or O(C═O)CH₃;R³ is H, CH₃, or (C═O)CH₃;R⁴ is H or optionally substituted alkyl; wherein said substituents areindependently selected from the group OR³ and (C═O)OR⁵;R⁵ is optionally substituted alkyl, cycloalkyl, phenylalkyl,heteroalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein saidsubstituents are independently (CH₂)_(n)CO₂alkyl;R⁶ is H or R⁵;R⁷ is H or R⁵;R⁸ is H or R⁵;R⁹ is 4-isoxazoyl;wherein n is an integer from 1-12; andA is an anion selected from the group consisting of: Br⁻, Cl⁻, I⁻, R⁷CO₂⁻, H₂PO₄ ⁻, NO₃ ⁻, Etodolate, Mefenamate, Urosodeoxycholate and R⁶SO₃.

Alkyl means unsubstituted and substituted, straight-chain andbranched-chain alkyls having from 1 to 20 carbon atoms; alkyl may alsocontain one or multiple numbers of unsaturation including double and/ortriple bonds; straight chain alkyl includes methyl, ethyl, propyl, butylgroup, pentyl (to be also referred to as an amyl group) hexyl, decyl),branched chain alkyl group includes isopropyl, diethylmethyl, isobutyl,sec-butyl, t-butyl, isopentyl, t-pentyl, 2-ethylhexyl and the like;alkyl is also optionally substituted with 1 or more substituentsindependently selected from the group consisting of halo, hydroxy,alkoxy(alkoxy)x, hydroxyalkoxy(alkoxy)x, amino, monoalkylamino,dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano, wherein x isan integer from 0 to 3 and the alkoxy contains from 1 to 5 carbon atoms.

Cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;and said cyclic alkyl is optionally substituted with 1 or 2 substituentsindependently selected from the group consisting of halo, hydroxy,alkoxy(alkoxy)x, hydroxyalkoxy(alkoxy)x, amino, monoalkylamino,dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano, wherein x isan integer from 0 to 3 and the alkoxy portion of the alkoxycarbonylcontains from 1 to 5 carbon atoms.

Phenylalkyl is selected from the group consisting of benzyl, phenylethyland phenylpropyl; and the phenyl portion of the phenylalkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of alkyl, hydroxy, alkoxy, halo, amino,monoalkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano,wherein the phenyl portion of the phenylalkyl is unsubstituted orsubstituted.

Heteroalkyl means a straight or branched-chain having from one to 20carbon atoms and one or more heteroatoms selected from nitrogen, oxygen,or sulphur, wherein the nitrogen and sulphur atoms may optionally beoxidized, i.e., in the form of an N-oxide or an S-oxide.

Heterocycloalkyl means a monocyclic or multicyclic ring system (whichmay be saturated or partially unsaturated), including fused and spirorings, of about five to about 10 elements wherein one or more of theelements in the ring system is an element other than carbon and isselected from nitrogen, oxygen, silicon, or sulphur atoms.

Aryl means phenyl or napthyl wherein the phenyl or napthyl moiety isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of alkyl, hydroxy, alkoxy, halo, amino,monoalkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyanogroups.

Heteroaryl means a five to about a 14-membered aromatic monocyclic ormulticyclic hydrocarbon ring system, including fused and spiro rings, inwhich one or more of the elements in the ring system is an element otherthan carbon and is selected from nitrogen, oxygen, silicon, or sulphurand wherein an N atom may be in the form of an N-oxide.

Natural, synthetic, racemic, L-, or D-amino acid group as used hereinrefers to a substituent containing 1 to 20 amino acid. When two or moreamino acids are linked together the group is known as a polypeptide. Thepolypeptide may be (i) an oligopeptide, (ii) a homopolymer of one of thetwenty naturally occurring amino acids, (iii) a heteropolymer of two ormore naturally occurring amino acids, (iv) a homopolymer of a syntheticamino acid, (v) a heteropolymer of two or more synthetic amino acids or(vi) a heteropolymer of one or more naturally occurring amino acids andone or more synthetic amino acids. Polypeptides include the twentynaturally occurring amino acids. Specific polypeptides include one ormore amino acids selected from glutamic acid, aspartic acid, arginine,asparagine, cysteine, lysine, threonine, or serine. Such peptides may beattached through the C-terminus or the N-terminus.

Selection of the particular amino acids will depend on the physicalproperties desired. For instance, properties such as bulk,lipophilicity, and hydrophilicity may be optimized according toselection parameters known to those skilled in the art.

Sugar or saccharide as used herein refers to a monosaccharide, adisaccharide, polysaccharide or sugar alcohol. Saccharide includesgalactose, fructose, glucose, maltose, cellobiose, gentiobiose,melibiose, lactose, turanose, sophorose, trehalose, isotrehalose,isosaccharose, white sugar, mannitol, sorbitol, xylitol or inositol.

Compounds of Formula I exist in the form of quaternary ammonium cationsionically complexed with pharmaceutically acceptable anions derived fromacids to form addition salts of the compounds of Formula I. The phrase“pharmaceutically acceptable salt(s)”, as used herein, unless otherwiseindicated, includes salts of quaternary ammonium compounds of Formula I.

Suitable salts are formed from acids which form non-toxic salts and mayinclude acids that are known to enhance the pharmacologic utility ofopioids. Examples include the acetate, adipate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,chenodeoxycholate, citrate, cyclamate, edisylate, Etodolate, esylate,formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mefenamate, mesylate, methylsulphate, naphthylate,2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,salycilate, saccharate, stearate, succinate, tannate, tartrate,tosylate, trifluoroacetate, Ursodexoycholate and xinofoate salts.Suitable anions include Br⁻, Cl⁻, I⁻, R⁷CO₂ ⁻, H₂PO₄ ⁻, NO₃ ⁻, andR⁶SO₃. Hemisalts may also be formed, for example, hemisulphate. For areview on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

As used herein the term “Formula I” is defined to include all forms ofthe compounds of Formula I, including hydrates, solvates, isomers,crystalline and non-crystalline forms, isomorphs, polymorphs, andmetabolites thereof.

The compounds of the present disclosure may exist in a continuum ofsolid states ranging from fully amorphous to fully crystalline. The term‘amorphous’ refers to a state in which the material lacks long rangeorder at the molecular level and, depending upon temperature, mayexhibit the physical properties of a solid or a liquid. Typically suchmaterials do not give distinctive X-ray diffraction patterns and, whileexhibiting the properties of a solid, are more formally described as aliquid. Upon heating, a change from solid to liquid properties occurswhich is characterized by a change of state, typically second order(‘glass transition’). The term ‘crystalline’ refers to a solid phase inwhich the material has a regular ordered internal structure at themolecular level and gives a distinctive X-ray diffraction pattern withdefined peaks. Such materials when heated sufficiently will also exhibitthe properties of a liquid, but the change from solid to liquid ischaracterized by a phase change, typically first order (‘meltingpoint’).

The compounds of the present disclosure may also exist in unsolvated andsolvated forms. The term ‘solvate’ is used herein to describe amolecular complex comprising the compound according to the presentdisclosure and one or more pharmaceutically acceptable solventmolecules, for example, ethanol. The term ‘hydrate’ is employed whensaid solvent is water.

A currently accepted classification system for organic hydrates is onethat defines isolated site, channel, or metal-ion coordinatedhydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones inwhich the water molecules are isolated from direct contact with eachother by intervening organic molecules. In channel hydrates, the watermolecules lie in lattice channels where they are next to other watermolecules. In metal-ion coordinated hydrates, the water molecules arebonded to the metal ion.

When the solvent or water is tightly bound, the complex will have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content will be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the aspects of the disclosed embodiments aremulti-component complexes (other than salts and solvates) wherein thedrug and at least one other component are present in stoichiometric ornon-stoichiometric amounts. Complexes of this type include clathrates(drug-host inclusion complexes) and co-crystals. The latter aretypically defined as crystalline complexes of neutral molecularconstituents which are bound together through non-covalent interactions,but could also be a complex of a neutral molecule with a salt.Co-crystals may be prepared by melt crystallisation, byrecrystallisation from solvents, or by physically grinding thecomponents together—see Chem Commun, 17, 1889-1896, by O. Almarsson andM. J. Zaworotko (2004). For a general review of multi-componentcomplexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August1975).

The compounds according to the disclosed embodiments may also exist in amesomorphic state (mesophase or liquid crystal) when subjected tosuitable conditions. The mesomorphic state is intermediate between thetrue crystalline state and the true liquid state (either melt orsolution). Mesomorphism arising as the result of a change in temperatureis described as ‘thermotropic’ and that resulting from the addition of asecond component, such as water or another solvent, is described as‘lyotropic’. Compounds that have the potential to form lyotropicmesophases are described as ‘amphiphilic’ and consist of molecules whichpossess an ionic (such as —COO⁻Na⁺, —COO⁻K⁺, or —SO₃ ⁻Na⁺) or non-ionic(such as —N⁻N⁺(CH₃)₃) polar head group. For more information, seeCrystals and the Polarizing Microscope by N. H. Hartshorne and A.Stuart, 4^(th) Edition (Edward Arnold, 1970).

Hereinafter all references to compounds of Formula I include referencesto salts, solvates, multi-component complexes and liquid crystalsthereof and to solvates, multi-component complexes and liquid crystalsof salts thereof.

The compounds of the present disclosure include compounds of Formula Ias hereinbefore defined, including all polymorphs and crystal habitsthereof, and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of Formula I.

The compounds of Formula I have asymmetric carbon and nitrogen atoms andexist as two or more stereoisomers. The bonds of the compounds ofFormula I may be depicted herein using a solid line (

), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g. specificenantiomers, racemic mixtures, etc.) at that atom are included. The useof either a solid or dotted wedge to depict bonds to asymmetric atoms ismeant to indicate that only the stereoisomer shown is meant to beincluded. It is possible that compounds of Formula I may contain morethan one asymmetric atom. In those compounds, the use of a solid line todepict bonds to asymmetric atoms is meant to indicate that all possiblestereoisomers are meant to be included. For example, unless statedotherwise, it is intended that the compounds of Formula I can exist asenantiomers and diastereomers or as racemates and mixtures thereof. Theuse of a solid line to depict bonds to one or more asymmetric atoms in acompound of Formula I and the use of a solid or dotted wedge to depictbonds to other asymmetric atoms in the same compound is meant toindicate that a mixture of diastereomers is present.

Stereoisomers of Formula I include cis and trans isomers, opticalisomers such as R and S enantiomers, diastereomers, geometric isomers,rotational isomers, conformational isomers, and tautomers of thecompounds of Formula I, including compounds exhibiting more than onetype of isomerism; and mixtures thereof (such as racemates anddiastereomeric pairs).

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

The compounds of the Formula I may exhibit the phenomena of tautomerismand structural isomerism. For example, the compounds of Formula I mayexist in several tautomeric forms, including the enol and imine form,and the keto and enamine form and geometric isomers and mixturesthereof. All such tautomeric forms are included within the scope ofcompounds of Formula I. Tautomers exist as mixtures of a tautomeric setin solution. In solid form, usually one tautomer predominates. Eventhough one tautomer may be described, the disclosed embodiments includeall tautomers of the compounds of Formula I.

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of Formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of thepresent disclosure include isotopes of hydrogen, such as ²H and ³H,carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, suchas ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N,oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur,such as ³⁵S.

Certain isotopically-labelled compounds of Formula I, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of Formula I can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagent in placeof the non-labeled reagent previously employed.

Another embodiment relates to compounds of Formula I, wherein thestereochemistry about the quaternary nitrogen center is in the “S”configuration.

Another embodiment relates to compounds of Formula I, wherein thestereochemistry about the quaternary nitrogen center is in the “R”configuration.

Compounds of Formula I of particular interest can be segregatedaccording to established opioid skeletons (wherein R² and R³ groups havebeen replaced) as described below:

Another embodiment of the present disclosure refers to compounds ofFormula I wherein the R¹ groups (taken together with the R⁴, R⁵ and R⁶functionality) have the formulae:

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴O(C═O)OR⁵.

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴O(C═O)R⁶.

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴O(C═O)NR⁶R⁷.

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴O(C═O)CHR⁸NR⁶R⁷.

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴O(C═O)CHR⁸NH(COCHR⁸NH)_(n)H.

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴R⁹.

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴O(C═O)CR⁵R⁶OR⁷.

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴O(C═O)O(CH₂)_(n)NR⁵R⁶.

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴O(C═O)O(CH₂)_(n)CO₂R⁵.

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴O(C═O)(CH₂)_(n)NR⁵R⁶.

Another embodiment relates to compounds of Formula I, wherein R¹ isCHR⁴O(C═O)(CH₂)_(n)CO₂R⁵.

Another embodiment relates to compounds of Formula I, wherein R¹ is

Another embodiment relates to compounds of Formula I, wherein R¹ is

Another embodiment relates to compounds of Formula I, wherein R² is H.Other embodiments relate to compounds of Formula I, wherein R² is H andR¹ is one of the aforesaid embodiments relating to R¹.

Another embodiment relates to compounds of Formula I, wherein R² is OH.Other embodiments relate to compounds of Formula I, wherein R² is OH andR¹ is one of the aforesaid embodiments relating to R¹.

Another embodiment relates to compounds of Formula I, wherein R² isO(C═O)CH₃. Other embodiments relate to compounds of Formula I, whereinR² is O(C═O)CH₃ and R¹ is one of the aforesaid embodiments relating toR¹.

Another embodiment relates to compounds of Formula I, wherein R³ is H.Other embodiments relate to compounds of Formula I, wherein R³ is H andR¹ is one of the aforesaid embodiments relating to R¹. Other embodimentsrelate to compounds of Formula I, wherein R³ is H and R¹ is one of theaforesaid embodiments relating to R¹ and/or R² is one of the aforesaidembodiments relating to R².

Another embodiment relates to compounds of Formula I, wherein R³ isMethyl. Other embodiments relate to compounds of Formula I, wherein R³is methyl and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, wherein R³ is methyland R¹ is one of the aforesaid embodiments relating to R¹ and/or R² isone of the aforesaid embodiments relating to R².

Another embodiment relates to compounds of Formula I, wherein R³ is(C═O)CH₃. Other embodiments relate to compounds of Formula I, wherein R³is (C═O)CH₃ and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, wherein R³ is(C═O)CH₃ and R¹ is one of the aforesaid embodiments relating to R¹and/or R² is one of the aforesaid embodiments relating to R².

Another embodiment relates to compounds of Formula I, wherein R⁴ is H.Other embodiments relate to compounds of Formula I, wherein R⁴ is H andR¹ is one of the aforesaid embodiments relating to R¹. Other embodimentsrelate to compounds of Formula I, wherein R⁴ is H and/or R¹ is one ofthe aforesaid embodiments relating to R¹ and/or R² is one of theaforesaid embodiments relating to R² and/or R³ is one of the aforesaidembodiments relating to R³.

Another embodiment relates to compounds of Formula I, wherein R⁴ ismethyl, ethyl, isopropyl, t-butyl, diethylmethyl, or pentyl. Otherembodiments relate to compounds of Formula I, wherein R⁴ is methyl,ethyl, isopropyl, t-butyl, diethylmethyl, or pentyl and R¹ is one of theaforesaid embodiments relating to R¹. Other embodiments relate tocompounds of Formula I, wherein R⁴ is methyl, ethyl, isopropyl, t-butyl,diethylmethyl, or pentyl and/or R¹ is one of the aforesaid embodimentsrelating to R¹ and/or R² is one of the aforesaid embodiments relating toR² and/or R³ is one of the aforesaid embodiments relating to R³.

Another embodiment relates to compounds of Formula I, wherein R⁴ isalkyl optionally substituted with one or more substituents independentlyselected from the group OR³ and (C═O)OR⁵. Other embodiments relate tocompounds of Formula I, wherein R⁴ is alkyl optionally substituted withone or more substituents independently selected from the group OR³ and(C═O)OR⁵ and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, wherein R⁴ is alkyloptionally substituted with one or more substituents independentlyselected from the group OR³ and (C═O)OR⁵ and/or R¹ is one of theaforesaid embodiments relating to R¹ and/or R² is one of the aforesaidembodiments relating to R² and/or R³ is one of the aforesaid embodimentsrelating to R³.

Another embodiment relates to compounds of Formula I, wherein R⁵ isalkyl selected from methyl, ethyl, isopropyl, n-butyl, or n-pentyl.Other embodiments relate to compounds of Formula I, wherein R⁵ is alkylselected from methyl, ethyl, isopropyl, n-butyl, or n-pentyl and R¹ isone of the aforesaid embodiments relating to R¹. Other embodimentsrelate to compounds of Formula I, wherein R⁵ is alkyl selected frommethyl, ethyl, isopropyl, n-butyl, or n-pentyl and/or R¹ is one of theaforesaid embodiments relating to R¹ and/or R² is one of the aforesaidembodiments relating to R² and/or R³ is one of the aforesaid embodimentsrelating to R³ and/or R⁴ is one of the aforesaid embodiments relating toR⁴.

Another embodiment relates to compounds of Formula I, wherein R⁵ isoptionally substituted alkyl, wherein said substituent(s) is(CH₂)_(n)CO₂alkyl; and wherein n is an integer from 1-12. Otherembodiments relate to compounds of Formula I, wherein R⁵ is optionallysubstituted alkyl, wherein said substituent(s) is (CH₂)_(n)CO₂alkyl; andwherein n is an integer from 1-12 and R¹ is one of the aforesaidembodiments relating to R¹. Other embodiments relate to compounds ofFormula I, wherein R⁵ is optionally substituted alkyl, wherein saidsubstituent(s) is (CH₂)_(n)CO₂alkyl; and wherein n is an integer from1-12 and/or R¹ is one of the aforesaid embodiments relating to R¹ and/orR² is one of the aforesaid embodiments relating to R² and/or R³ is oneof the aforesaid embodiments relating to R³ and/or R⁴ is one of theaforesaid embodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁵ iscyclohexyl. Other embodiments relate to compounds of Formula I, whereinR⁵ is cyclohexyl and R¹ is one of the aforesaid embodiments relating toR¹. Other embodiments relate to compounds of Formula I, R⁵ is cyclohexyland/or R¹ is one of the aforesaid embodiments relating to R¹ and/or R²is one of the aforesaid embodiments relating to R² and/or R³ is one ofthe aforesaid embodiments relating to R³ and/or R⁴ is one of theaforesaid embodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁵ isbenzyl. Other embodiments relate to compounds of Formula I, wherein R⁵is benzyl and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, R⁵ is benzyl and/orR¹ is one of the aforesaid embodiments relating to R¹ and/or R² is oneof the aforesaid embodiments relating to R² and/or R³ is one of theaforesaid embodiments relating to R³ and/or R⁴ is one of the aforesaidembodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁶ is H.Other embodiments relate to compounds of Formula I, wherein R⁶ is H andR¹ is one of the aforesaid embodiments relating to R¹. Other embodimentsrelate to compounds of Formula I, wherein R⁶ is H and/or R¹ is one ofthe aforesaid embodiments relating to R¹ and/or R² is one of theaforesaid embodiments relating to R² and/or R³ is one of the aforesaidembodiments relating to R³ and/or R⁴ is one of the aforesaid embodimentsrelating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁶ ismethyl. Other embodiments relate to compounds of Formula I, wherein R⁶is methyl and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, R⁶ is methyl and/orR¹ is one of the aforesaid embodiments relating to R¹ and/or R² is oneof the aforesaid embodiments relating to R² and/or R³ is one of theaforesaid embodiments relating to R³ and/or R⁴ is one of the aforesaidembodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁶ ist-butyl. Other embodiments relate to compounds of Formula I, wherein R⁶is t-butyl and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, wherein R⁶ ist-butyl and/or R¹ is one of the aforesaid embodiments relating to R¹and/or R² is one of the aforesaid embodiments relating to R² and/or R³is one of the aforesaid embodiments relating to R³ and/or R⁴ is one ofthe aforesaid embodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁶ isi-propyl. Other embodiments relate to compounds of Formula I, wherein R⁶is i-propyl and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, R⁶ is i-propyland/or R¹ is one of the aforesaid embodiments relating to R¹ and/or R²is one of the aforesaid embodiments relating to R² and/or R³ is one ofthe aforesaid embodiments relating to R³ and/or R⁴ is one of theaforesaid embodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁶ iscyclohexyl. Other embodiments relate to compounds of Formula I, whereinR⁶ is cyclohexyl and R¹ is one of the aforesaid embodiments relating toR¹. Other embodiments relate to compounds of Formula I, wherein R⁶ iscyclohexyl and/or R¹ is one of the aforesaid embodiments relating to R¹and/or R² is one of the aforesaid embodiments relating to R² and/or R³is one of the aforesaid embodiments relating to R³ and/or R⁴ is one ofthe aforesaid embodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁶ isbenzyl. Other embodiments relate to compounds of Formula I, wherein R⁶is benzyl and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, R⁶ is benzyl and/orR¹ is one of the aforesaid embodiments relating to R¹ and/or R² is oneof the aforesaid embodiments relating to R² and/or R³ is one of theaforesaid embodiments relating to R³ and/or R⁴ is one of the aforesaidembodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁶ isphenyl. Other embodiments relate to compounds of Formula I, wherein R⁶is phenyl and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, wherein R⁶ is phenyland/or R¹ is one of the aforesaid embodiments relating to R¹ and/or R²is one of the aforesaid embodiments relating to R² and/or R³ is one ofthe aforesaid embodiments relating to R³ and/or R⁴ is one of theaforesaid embodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁷ is H.Other embodiments relate to compounds of Formula I, wherein R⁷ is H andR¹ is one of the aforesaid embodiments relating to R¹. Other embodimentsrelate to compounds of Formula I, wherein R⁷ is H and/or R¹ is one ofthe aforesaid embodiments relating to R¹ and/or R² is one of theaforesaid embodiments relating to R² and/or R³ is one of the aforesaidembodiments relating to R³ and/or R⁴ is one of the aforesaid embodimentsrelating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁷ ismethyl. Other embodiments relate to compounds of Formula I, wherein R⁷is methyl and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, wherein R⁷ is methyland/or R¹ is one of the aforesaid embodiments relating to R¹ and/or R²is one of the aforesaid embodiments relating to R² and/or R³ is one ofthe aforesaid embodiments relating to R³ and/or R⁴ is one of theaforesaid embodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁶ is H.Other embodiments relate to compounds of Formula I, wherein R⁸ is H andR¹ is one of the aforesaid embodiments relating to R¹. Other embodimentsrelate to compounds of Formula I, wherein R⁸ is H and/or R¹ is one ofthe aforesaid embodiments relating to R¹ and/or R² is one of theaforesaid embodiments relating to R² and/or R³ is one of the aforesaidembodiments relating to R³ and/or R⁴ is one of the aforesaid embodimentsrelating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁸ ismethyl. Other embodiments relate to compounds of Formula I, wherein R⁸is methyl and R¹ is one of the aforesaid embodiments relating to R¹.Other embodiments relate to compounds of Formula I, wherein R⁸ is methyland/or R¹ is one of the aforesaid embodiments relating to R¹ and/or R²is one of the aforesaid embodiments relating to R² and/or R³ is one ofthe aforesaid embodiments relating to R³ and/or R⁴ is one of theaforesaid embodiments relating to R⁴.

Another embodiment relates to compounds of Formula I, wherein R⁹ is4-isoxazoyl. Other embodiments relate to said R⁹ 4-isoxazoyl embodimentstaken in combination with the R¹, R², R³, R⁴ and/or R⁵ embodimentsdescribed herein above.

Another embodiment relates to compounds of Formula I, wherein A is Br⁻.Other embodiments relate to said A as Br⁻ embodiments taken incombination with the other R¹, R², R³, R⁴ and/or R⁵ embodimentsdescribed herein above.

Another embodiment relates to compounds of Formula I, wherein A is Cl⁻.Other embodiments relate to said A is Cl⁻ embodiments taken incombination with the other R¹, R², R³, R⁴ and/or R⁵ embodimentsdescribed herein above.

Another embodiment relates to compounds of Formula I, wherein A is I⁻.Other embodiments relate to said A is I⁻ embodiments taken incombination with the other R¹, R², R³, R⁴ and/or R⁵ embodimentsdescribed herein above.

Another embodiment relates to compounds of Formula I, wherein A is R⁷CO₂⁻, more specifically lactate, acetate, tartrate, and valerate. Otherembodiments relate to said A is R⁷CO₂ ⁻ embodiments taken in combinationwith the other R¹, R², R³, R⁴ and/or R⁵ embodiments. described hereinabove.

Another embodiment relates to compounds of Formula I, wherein A is H₂PO₄⁻. Other embodiments relate to said A as H₂PO₄ ⁻ embodiments taken incombination with the other R¹, R², R³, R⁴ and/or R⁵ embodimentsdescribed herein above.

Another embodiment relates to compounds of Formula I, wherein A is NO₃⁻. Other embodiments relate to said A as NO₃ ⁻ embodiments taken incombination with the other R¹, R², R³, R⁴ and/or R⁵ embodimentsdescribed herein above.

Another embodiment relates to compounds of Formula I, wherein A isR⁶SO₃. Other embodiments relate to said A as R⁶SO₃ embodiments taken incombination with the other R¹, R², R³, R⁴ and/or R⁵ embodimentsdescribed herein above.

Another embodiment relates to compounds of Formula I, wherein A isUrsodeoxycholate. Other embodiments relate to said A as Ursodeoxycholateembodiments taken in combination with the other R¹, R², R³, R⁴ and/or R⁵embodiments described herein above.

Another embodiment relates to compounds of Formula I, wherein A isEtodolate. Other embodiments relate to said A as Etodolate embodimentstaken in combination with the other R¹, R², R³, R⁴ and/or R⁵ embodimentsdescribed herein above.

Another embodiment relates to compounds of Formula I, wherein A isMefanamate. Other embodiments relate to said A as Mefanamate embodimentstaken in combination with the other R¹, R², R³, R⁴ and/or R⁵ embodimentsdescribed herein above.

Another embodiment of the invention relates to the following specificcompounds of the invention:

The compounds of Formula I (and the other embodiments above) are usefulin the treatment of pain, particularly neuropathic, nociceptive andinflammatory pain.

Another embodiment relates to a method of treating acute or chronic paincomprising administering to a patient an effective amount of a compoundof Formula I.

The aspects of the disclosed embodiments also relate to compositionscomprising a compound of Formula I. Accordingly one embodiment relatesto a pharmaceutical composition comprising a pharmaceutically effectiveamount of a compound of Formula I, a pharmaceutically acceptable carrierand, optionally, at least one additional medicinal or pharmaceuticalagent.

Another embodiment relates to a composition of any of the aforesaidembodiments of compounds of Formula I wherein said composition is intablet, capsule, oral solution, or oral suspension dosage form.

Another embodiment relates to a composition of a compound of Formula Iwherein said composition is in tablet or capsule dosage form.

Another embodiment relates to an oral pharmaceutical preparationcontaining a therapeutically effective amount of a compound of Formula Ifor once daily administration.

Another embodiment relates to a sustained release composition containinga compound of Formula I.

In yet further embodiments, the pharmaceutical composition in additionto the compound of Formula I may further include a non-opioid drug. Suchnon-opioid drugs would preferably provide additional analgesia, andinclude, for example, aspirin; acetaminophen; non-steroidalanti-inflammatory drugs (“NSAIDS”), e.g., ibuprofen, ketoprofen, etc.;N-methyl-D-aspartate (NMDA) receptor antagonists, e.g., a morphinan suchas dextromethorphan or dextrorphan, or ketamine; cyclooxygenase-IIinhibitors (“COX-II inhibitors”); and/or glycine receptor antagonists.

Suitable non-steroidal anti-inflammatory agents, include ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam,pharmaceutically acceptable salts thereof, mixtures thereof, and thelike. Useful dosages of these drugs are well known to those skilled inthe art.

N-methyl-D-aspartate (NMDA) receptor antagonists are well known in theart, and encompass, for example, morphinans such as dextromethorphan ordextrorphan, ketamine, or pharmaceutically acceptable salts thereof. Forpurposes of the present disclosure, the term “NMDA antagonist” is alsodeemed to encompass drugs that at least partially inhibit a majorintracellular consequence of NMDA-receptor activation, e.g. aganglioside such as GM.sub.1 or GT.sub.1 b, a phenothiazine such astrifluoperazine or a naphthalenesulfonamide such asN-(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al.),and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.).The NMDA antagonist may be included alone, or in combination with alocal anesthetic such as lidocaine, as described in these Mayer, et al.patents.

The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber, et al.).

COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995;5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and5,130,311. Certain preferred COX-2 inhibitors include celecoxib,flosulide, meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA),nabumetone (prodrug for 6-MNA), nimesulide, or combinations thereof.Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg toabout 140 mg per kilogram of body weight per day are therapeuticallyeffective in combination with the compounds of Formula I. Alternatively,about 0.25 mg to about 7 g per patient per day of a COX-2 inhibitor isadministered in a combination.

In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, antihistamine drugs, local anesthetics, andthe like.

The pharmaceutically acceptable carrier may comprise any conventionalpharmaceutical carrier or excipient. Suitable pharmaceutical carriersinclude inert diluents or fillers, water and various organic solvents(such as hydrates and solvates). The pharmaceutical compositions may, ifdesired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Non-limiting examples ofmaterials, therefore, include lactose or milk sugar and high molecularweight polyethylene glycols.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution suspension, for parenteral injection as asterile solution, suspension or emulsion, for topical administration asan ointment or cream or for rectal administration as a suppository.

Physiological pain is an important protective mechanism designed to warnof danger from potentially injurious stimuli from the externalenvironment. The system operates through a specific set of primarysensory neurons and is activated by noxious stimuli via peripheraltransducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164for a review). These sensory fibers are known as nociceptors and arecharacteristically small diameter axons with slow conduction velocities.Nociceptors encode the intensity, duration and quality of noxiousstimulus and by virtue of their topographically organized projection tothe spinal cord, the location of the stimulus. The nociceptors are foundon nociceptive nerve fibers of which there are two main types, A-deltafibres (myelinated) and C fibres (non-myelinated). The activitygenerated by nociceptor input is transferred, after complex processingin the dorsal horn, either directly, or via brain stem relay nuclei, tothe ventrobasal thalamus and then on to the cortex, where the sensationof pain is generated.

Pain may generally be classified as acute or chronic. Acute pain beginssuddenly and is short-lived (usually twelve weeks or less). It isusually associated with a specific cause such as a specific injury andis often sharp and severe. It is the kind of pain that can occur afterspecific injuries resulting from surgery, dental work, a strain or asprain. Acute pain does not generally result in any persistentpsychological response. In contrast, chronic pain is long-term pain,typically persisting for more than three months and leading tosignificant psychological and emotional problems. Common examples ofchronic pain are neuropathic pain (e.g. painful diabetic neuropathy,post herpetic neuralgia), carpal tunnel syndrome, back pain, headache,cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma,the characteristics of nociceptor activation are altered and there issensitization in the periphery, locally around the injury and centrallywhere the nociceptors terminate. These effects lead to a heightenedsensation of pain. In acute pain these mechanisms can be useful, inpromoting protective behaviors which may better enable repair processesto take place. The normal expectation would be that sensitivity returnsto normal once the injury has healed. However, in many chronic painstates, the hypersensitivity far outlasts the healing process and isoften due to nervous system injury. This injury often leads toabnormalities in sensory nerve fibers associated with maladaptation andaberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivityfeature among the patient's symptoms. Patients tend to be quiteheterogeneous and may present with various pain symptoms. Such symptomsinclude: 1) spontaneous pain which may be dull, burning, or stabbing; 2)exaggerated pain responses to noxious stimuli (hyperalgesia); and 3)pain produced by normally innocuous stimuli (allodynia—Meyer et al.,1994, Textbook of Pain, 13-44). Although patients suffering from variousforms of acute and chronic pain may have similar symptoms, theunderlying mechanisms may be different and may, therefore, requiredifferent treatment strategies. Pain can also therefore be divided intoa number of different subtypes according to differing pathophysiology,including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli withthe potential to cause injury. Pain afferents are activated bytransduction of stimuli by nociceptors at the site of injury andactivate neurons in the spinal cord at the level of their termination.This is then relayed up the spinal tracts to the brain where pain isperceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activationof nociceptors activates two types of afferent nerve fibers. MyelinatedA-delta fibers transmit rapidly and are responsible for sharp andstabbing pain sensations, whilst unmyelinated C fibers transmit at aslower rate and convey a dull or aching pain. Moderate to severe acutenociceptive pain is a prominent feature of pain from central nervoussystem trauma, strains/sprains, burns, myocardial infarction and acutepancreatitis, post-operative pain (pain following any type of surgicalprocedure), posttraumatic pain, renal colic, cancer pain and back pain.Cancer pain may be chronic pain such as tumor related pain (e.g. bonepain, headache, facial pain or visceral pain) or pain associated withcancer therapy (e.g. post chemotherapy syndrome, chronic postsurgicalpain syndrome or post radiation syndrome). Cancer pain may also occur inresponse to chemotherapy, immunotherapy, hormonal therapy orradiotherapy. Back pain may be due to herniated or rupturedintervertebral discs or abnormalities of the lumber facet joints,sacroiliac joints, paraspinal muscles or the posterior longitudinalligament. Back pain may resolve naturally but in some patients, where itlasts over 12 weeks, it becomes a chronic condition which can beparticularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by aprimary lesion or dysfunction in the nervous system. Nerve damage can becaused by trauma and disease and thus the term ‘neuropathic pain’encompasses many disorders with diverse etiologies. These include, butare not limited to, peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy,HIV neuropathy, phantom limb pain, carpal tunnel syndrome, centralpost-stroke pain and pain associated with chronic alcoholism,hypothyroidism, uremia, multiple sclerosis, spinal cord injury,Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic painis pathological as it has no protective role. It is often present wellafter the original cause has dissipated, commonly lasting for years,significantly decreasing a patient's quality of life (Woolf and Mannion,1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain aredifficult to treat, as they are often heterogeneous even betweenpatients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6,S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). Theyinclude spontaneous pain, which can be continuous, and paroxysmal orabnormal evoked pain, such as hyperalgesia (increased sensitivity to anoxious stimulus) and allodynia (sensitivity to a normally innocuousstimulus).

The inflammatory process is a complex series of biochemical and cellularevents, activated in response to tissue injury or the presence offoreign substances, which results in swelling and pain (Levine andTaiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most commoninflammatory pain. Rheumatoid disease is one of the commonest chronicinflammatory conditions in developed countries and rheumatoid arthritisis a common cause of disability. The exact etiology of rheumatoidarthritis is unknown, but current hypotheses suggest that both geneticand microbiological factors may be important (Grennan & Jayson, 1994,Textbook of Pain, 397-407). It has been estimated that almost 16 millionAmericans have symptomatic osteoarthritis (OA) or degenerative jointdisease, most of whom are over 60 years of age, and this is expected toincrease to 40 million as the age of the population increases, makingthis a public health problem of enormous magnitude (Houge & Mersfelder,2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook ofPain, 387-395). Most patients with osteoarthritis seek medical attentionbecause of the associated pain. Arthritis has a significant impact onpsychosocial and physical function and is known to be the leading causeof disability in later life. Ankylosing spondylitis is also a rheumaticdisease that causes arthritis of the spine and sacroiliac joints. Itvaries from intermittent episodes of back pain that occur throughoutlife to a severe chronic disease that attacks the spine, peripheraljoints and other body organs.

Another type of inflammatory pain is visceral pain which includes painassociated with inflammatory bowel disease (IBD). Visceral pain is painassociated with the viscera, which encompass the organs of the abdominalcavity. These organs include the sex organs, spleen and part of thedigestive system. Pain associated with the viscera can be divided intodigestive visceral pain and non-digestive visceral pain. Commonlyencountered gastrointestinal (GI) disorders that cause pain includefunctional bowel disorder (FBD) and inflammatory bowel disease (IBD).These GI disorders include a wide range of disease states that arecurrently only moderately controlled, including, in respect of FBD,gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) andfunctional abdominal pain syndrome (FAPS), and, in respect of IBD,Crohn's disease, ileitis and ulcerative colitis, all of which regularlyproduce visceral pain. Other types of visceral pain include the painassociated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple etiologies andthus can be classified in more than one area, e.g. back pain and cancerpain have both nociceptive and neuropathic components.

Other types of pain include: pain resulting from muscular-skeletaldisorders, including myalgia, fibromyalgia, spondylitis, sero-negative(non-rheumatoid) arthropathies, non-articular rheumatism,dystrophinopathy, glycogenolysis, polymyositis and pyomyositis; heartand vascular pain, including pain caused by angina, myocardicalinfarction, mitral stenosis, pericarditis, Raynaud's phenomenon,scleredoma and skeletal muscle ischemia; head pain, such as migraine(including migraine with aura and migraine without aura), clusterheadache, tension-type headache mixed headache and headache associatedwith vascular disorders; erythermalgia; and orofacial pain, includingdental pain, otic pain, burning mouth syndrome and temporomandibularmyofascial pain.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. The term “treating” alsoincludes adjuvant and neo-adjuvant treatment of a subject.

Administration of the compounds of Formula I may be effected by anymethod that enables delivery of the compounds to the site of action.These methods include oral routes, intraduodenal routes, parenteralinjection (including intravenous, subcutaneous, intramuscular,intravascular or infusion), topical, and rectal administration.

The aspects of the disclosed embodiments also relate to altering thepharmacokinetic and pharmacological properties of opioids, particularlyoxycodone, oxymorphone, hydrocodone and hydromorphone, throughquaternization of the bicyclic tertiary amine embedded in the opioidstructure. It is well known to those skilled in the art thatquaternization can change the rate and extent of absorption, metabolism,distribution, and elimination of a drug. Moreover, preferred quaternaryammonium compounds of the present disclosure possess opioid antagonistactivity. Furthermore, the quaternary ammonium compounds of thedisclosure, when ingested or administered to a patient by any othermeans, are converted to free base opioid possessing agonist activity atopioid receptors. Thus, these compounds inherently possess bothantagonist and agonist properties. When the quaternary ammonium compoundis first orally administered it may bind to opioid receptors. Morespecifically, if a quaternary ammonium compound of the disclosure isorally ingested, the compound upon reaching the intestinal tract bindsto the mu or delta opioid receptor acting as an antagonist.Simultaneously, quaternary ammonium opioid compound is subject to theaction of intestinal metabolic action and uptake and further metabolismby intestinal wall transmission processes. These processes areresponsible for converting the quaternary ammonium opioid into thetertiary amine parent compound (i.e. oxycodone, oxymorphone andhydromorphone). Although the opioid is now free to act in the intestinaltract as an agonist the receptors have already been blocked by priorsaturation with the antagonistic quaternary compound. This localizedinactivation of opioid receptors reduces local side effects such asconstipation, a major side effect of agonists. When administered at anormal therapeutic dose the bioavailability (thetime-versus-concentration curve; area under the curve; AUC) of theopioid may be similar to that observed with slow or extended releaseformulations of the parent free base opioid compound. However, since theuptake (systemic bioavailability) of the quaternary ammonium opioidderivative into the circulation is generally much lower when comparedwith the uptake of the parent opioid compounds, this differential uptakeproperty causes a relative decline of the parent opioid agonistconcentration in intestinal compartments and maintains the potential ofthe antagonist to reduce agonist induced constipation. In contrast, theparent opioid agonist derived from the quaternary ammonium precursorthrough the action of metabolic enzymes is readily taken up into thecirculation, enters the central nervous system where it exerts itsanalgesic activity. Moreover, the quaternary ammonium antagonist isrestricted from crossing the blood brain barrier and thus has negligiblepenetration into the central nervous system. Furthermore, since meansfor generating euphoria aim at very rapid delivery of relatively largeamounts of an opioid into the central nervous system; compounds embracedin general formula 1 are abuse resistant because enzymes control theamounts of opioid available for CNS uptake and the speed of release froma quaternary ammonium precursor cannot be altered even if compounds aretaken above doses intended in the prescription or in deviation of therecommended route of administration. Likewise, the active principal inopioid abuse cannot be easily obtained from quaternary ammoniumprecursors adding a second barrier to drug abuse. This in turndiminishes the abuse potential, whether unintended or intentionallysought.

Persons that abuse opioids such as hydrocodone or oxycodone commonlyseek to increase their euphoria by snorting or injecting the drugs.These routes of administration increase the rate and extent of drugabsorption and provide a faster, nearly instantaneous, effect. Thisincreases the amount of drug that reaches the central nervous systemwhere it has its effect. In a particular aspect of the disclosedembodiments, the bioavailability of the covalently modified opioid issubstantially decreased by the intranasal and intravenous routes ascompared to the parent opioid compound. Thus the illicit practice ofsnorting and shooting the drug loses its advantage.

Dosage regimens may be adjusted to provide the optimum desired response.For example, a single bolus may be administered, several divided dosesmay be administered over time or the dose may be proportionally reducedor increased as indicated by the exigencies of the therapeuticsituation. It is especially advantageous to formulate parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form, as used herein, refers tophysically discrete units suited as unitary dosages for the mammaliansubjects to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier.

Thus, the skilled artisan would appreciate, based upon the disclosureprovided herein, that the dose and dosing regimen is adjusted inaccordance with methods well-known in the therapeutic arts. That is, themaximum tolerable dose can be readily established, and the effectiveamount providing a detectable therapeutic benefit to a patient may alsobe determined, as can the temporal requirements for administering eachagent to provide a detectable therapeutic benefit to the patient.Accordingly, while certain dose and administration regimens areexemplified herein, these examples in no way limit the dose andadministration regimen that may be provided to a patient in practicingthe aspects of the disclosed embodiments.

It is to be noted that dosage values may vary with the type and severityof the condition to be alleviated, and may include single or multipledoses. It is to be further understood that for any particular subject,specific dosage regimens should be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition. Forexample, doses may be adjusted based on pharmacokinetic orpharmacodynamic parameters, which may include clinical effects such astoxic effects and/or laboratory values. Thus, the aspects of thedisclosed embodiments encompass intra-patient dose-escalation asdetermined by the skilled artisan. Determining appropriate dosages andregimens for administration of the active agent are well-known in therelevant art and would be understood to be encompassed by the skilledartisan once provided the teachings disclosed herein.

The amount of the compound of Formula I administered will be dependenton the subject being treated, the severity of the disorder or condition,the rate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to about 7 g/day,preferably about 0.1 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

As used herein, the term “combination therapy” refers to theadministration of a compound of Formula I together with an at least oneadditional pharmaceutical or medicinal agent, either sequentially orsimultaneously.

The aspects of the disclosed embodiments include the use of acombination of a compound as provided in Formula I and one or moreadditional pharmaceutically active agent(s). If a combination of activeagents is administered, then they may be administered sequentially orsimultaneously, in separate dosage forms or combined in a single dosageform. Accordingly, the present disclosure also includes pharmaceuticalcompositions comprising an amount of: (a) a first agent comprising acompound of Formula I; (b) a second pharmaceutically active agent; and(c) a pharmaceutically acceptable carrier, vehicle or diluent.

Various pharmaceutically active agents may be selected for use inconjunction with the compounds of Formula I, depending on the disease,disorder, or condition to be treated.

DETAILED DESCRIPTION

In the reaction schemes and Formulae that follow R¹ through R⁹, n, and Aare as defined above.

Compounds of the Formula I may be subcategorized into recognizedindividual opioid skeletons including oxycodone, hydrocodone,oxymorphone and hydromorphone as described above. Each of theseskeletons is associated with copious synthetic methods well known tothose skilled in the art. Thus starting materials of the Formula IV andV are commercially available or can be made by methods well known tothose skilled in the art. See for example U.S. Pat. No. 8,183,376, U.S.Pat. Nos. 2,628,962, 2,654,756 and 2,649,454 (hydromorphone and others);U.S. Pat. No. 2,715,626 (hydrocodone and others); U.S. Pat. No.2,806,033 (oxymorphone and others); Freund et al. (1916) J. Prak. Chemie94:135-178 (oxycodone).

In general the compounds of the disclosed embodiments may be made byprocesses which include processes analogous to those known in thechemical arts, particularly in light of the description containedherein. The compounds of the disclosed embodiments also have asymmetricnitrogen atoms and exist as two stereoisomers around the quaternaryammonium nitrogen. Other asymmetric carbon atoms exist in thesecompounds enlarging the number of possible stereoisomers.

Scheme 1 refers to the preparation of compounds of Formula I having the“S” stereochemistry about the quaternary ammonium nitrogen. Referring toScheme 1, compounds of Formula IV may be produced by reaction of freebase des-methyl opioid of Formula V, such as Norhydromorphone,Noroxymorphone, Noroxycodone, Norhydrocodone, with a halomethyl acetate,carbonate, carbamate, or isoxazolylate, such as chloromethyl acetate, inthe presence of a strong base, such as for example, NaH, LDA andKO^(t)Bu.

The alpha methyl acetate, carbonate, carbamate, or isoxazolylate(including derivatives of Formula II or III when using appropriateactivated reagents) compound of Formula IV may be reacted with amethylating agent such as methyl iodide in the presence of a base toform the “S” enantiomeric quaternary ammonium compound of Formula I.

Scheme 2 refers to the preparation of compounds of Formula I having the“R” stereochemistry about the quaternary ammonium nitrogen. Referring toScheme 2, free base opioid compounds of Formula IV may be reacted with ahalomethyl acetate, carbonate, carbamate, or isoxazolylate, such aschloromethyl acetate, in the presence of a strong base such as forexample, NaH, LDA, KO^(t)Bu to form a compound of Formula I.

As an initial note, in the preparation of the Formula I compounds it isnoted that some of the preparation methods useful for the preparation ofthe compounds described herein may require protection of remotefunctionality (e.g., primary amine, secondary amine, carboxyl in FormulaI precursors). The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. The need for such protection is readily determined by oneskilled in the art. The use of such protection/deprotection methods isalso within the skill in the art. For a general description ofprotecting groups and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

Compounds of Formula I that have chiral centers may exist asstereoisomers, such as racemates, enantiomers, or diastereomers.Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate using, for example, chiral highpressure liquid chromatography (HPLC). Alternatively, the racemate (or aracemic precursor) may be reacted with a suitable optically activecompound, for example, an alcohol, or, in the case where the compoundcontains an acidic or basic moiety, an acid or base such as tartaricacid or 1-phenylethylamine. The resulting diastereomeric mixture may beseparated by chromatography and/or fractional crystallization and one orboth of the diastereoisomers converted to the corresponding pureenantiomer(s) by means well known to one skilled in the art. Chiralcompounds of Formula I (and chiral precursors thereof) may be obtainedin enantiomerically-enriched form using chromatography, typically HPLC,on an asymmetric resin with a mobile phase consisting of a hydrocarbon,typically heptane or hexane, containing from 0 to 50% isopropanol,typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically0.1% diethylamine. Concentration of the eluate affords the enrichedmixture. Stereoisomeric conglomerates may be separated by conventionaltechniques known to those skilled in the art. See, e.g. “Stereochemistryof Organic Compounds” by E. L. Eliel (Wiley, New York, 1994), thedisclosure of which is incorporated herein by reference in its entirety.

Where a compound of Formula I contains an alkenyl or alkenylene group,geometric cis/trans (or Z/E) isomers are possible. Cis/trans isomers maybe separated by conventional techniques well known to those skilled inthe art, for example, chromatography and fractional crystallization.Salts of the present disclosure can be prepared according to methodsknown to those of skill in the art.

Polymorphs can be prepared according to techniques well-known to thoseskilled in the art.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Chiral compounds of the disclosed embodiments (and chiral precursorsthereof) may be obtained in enantiomerically-enriched form usingchromatography, typically HPLC, on an asymmetric resin with a mobilephase consisting of a hydrocarbon, typically heptane or hexane,containing from 0 to 50% by volume of isopropanol, typically from 2% to20%, and from 0 to 5% by volume of an alkylamine, typically 0.1%diethylamine. Concentration of the eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture haveidentical physical properties, they may have different physicalproperties compared to the true racemate. Racemic mixtures may beseparated by conventional techniques known to those skilled in theart—see, for example, Stereochemistry of Organic Compounds by E. L.Eliel and S. H. Wilen (Wiley, 1994).

The aspects of the disclosed embodiments also includeisotopically-labeled compounds of Formula I, wherein one or more atomsis replaced by an atom having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature. Isotopically-labeled compounds of Formula I cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed.

Compounds of the disclosed embodiments intended for pharmaceutical usemay be administered as crystalline or amorphous products. They may beobtained, for example, as solid plugs, powders, or films by methods suchas precipitation, crystallization, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

They may be administered alone or in combination with one or more othercompounds of the disclosed embodiments or in combination with one ormore other drugs (or as any combination thereof). Generally, they willbe administered as a formulation in association with one or morepharmaceutically acceptable excipients. The term ‘excipient’ is usedherein to describe any ingredient other than the compound(s) of thedisclosed embodiments. The choice of excipient will to a large extentdepend on factors such as the particular mode of administration, theeffect of the excipient on solubility and stability, and the nature ofthe dosage form.

Pharmaceutical compositions suitable for the delivery of compounds ofthe disclosed embodiments and methods for their preparation will bereadily apparent to those skilled in the art. Such compositions andmethods for their preparation may be found, for example, in Remington'sPharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

The compounds of the disclosed embodiments may be administered orally.Oral administration may involve swallowing, so that the compound entersthe gastrointestinal tract, and/or buccal, lingual, or sublingualadministration by which the compound enters the blood stream directlyfrom the mouth.

Formulations suitable for oral administration include solid, semi-solidand liquid systems such as tablets; soft or hard capsules containingmulti- or nano-particulates, liquids, or powders; lozenges (includingliquid-filled); chews; gels; fast dispersing dosage forms; films;ovules; sprays; and buccal/mucoadhesive patches.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsules(made, for example, from gelatin or hydroxypropylmethylcellulose) andtypically comprise a carrier, for example, water, ethanol, polyethyleneglycol, propylene glycol, methylcellulose, or a suitable oil, and one ormore emulsifying agents and/or suspending agents. Liquid formulationsmay also be prepared by the reconstitution of a solid, for example, froma sachet.

The compounds of the disclosed embodiments may also be used infast-dissolving, fast-disintegrating dosage forms such as thosedescribed in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, byLiang and Chen (2001).

For tablet dosage forms, depending on dose, the drug may make up from 1weight % to 80 weight % of the dosage form, more typically from 5 weight% to 60 weight % of the dosage form. In addition to the drug, tabletsgenerally contain a disintegrant. Examples of disintegrants includesodium starch glycolate, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, croscarmellose sodium, crospovidone,polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose,lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinisedstarch and sodium alginate. Generally, the disintegrant will comprisefrom 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight% of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise from0.2 weight % to 5 weight % of the tablet, and glidants may comprise from0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight %to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouringagents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight %to about 90 weight % binder, from about 0 weight % to about 85 weight %diluent, from about 2 weight % to about 10 weight % disintegrant, andfrom about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms:Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, NewYork, 1980).

Consumable oral films for human or veterinary use are typically pliablewater-soluble or water-swellable thin film dosage forms which may berapidly dissolving or mucoadhesive and typically comprise a compound offormula I, a film-forming polymer, a binder, a solvent, a humectant, aplasticiser, a stabiliser or emulsifier, a viscosity-modifying agent anda solvent. Some components of the formulation may perform more than onefunction.

The compound of formula I may be water-soluble or insoluble. Awater-soluble compound typically comprises from 1 weight % to 80 weight%, more typically from 20 weight % to 50 weight %, of the solutes. Lesssoluble compounds may comprise a greater proportion of the composition,typically up to 88 weight % of the solutes. Alternatively, the compoundof formula I may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides,proteins, or synthetic hydrocolloids and is typically present in therange 0.01 to 99 weight %, more typically in the range 30 to 80 weight%.

Other possible ingredients include anti-oxidants, colorants, flavouringsand flavour enhancers, preservatives, salivary stimulating agents,cooling agents, co-solvents (including oils), emollients, bulkingagents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the disclosed embodiments are typicallyprepared by evaporative drying of thin aqueous films coated onto apeelable backing support or paper. This may be done in a drying oven ortunnel, typically a combined coater dryer, or by freeze-drying orvacuuming.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulationsincluding delayed-, sustained-, pulsed-, controlled-, targeted andprogrammed release are of particular interest. Suitable modified releaseformulations for the purposes of the disclosed embodiments are describedin U.S. Pat. No. 6,106,864. Details of other suitable releasetechnologies such as high energy dispersions and osmotic and coatedparticles are to be found in Pharmaceutical Technology On-line, 25(2),1-14, by Verma et al (2001). The use of chewing gum to achievecontrolled release is described in WO 00/35298.

The compounds of the disclosed embodiments may also be administereddirectly into the blood stream, into muscle, or into an internal organ.Suitable means for parenteral administration include intravenous,intraarterial, intraperitoneal, intrathecal, intraventricular,intraurethral, intrasternal, intracranial, intramuscular, intrasynovialand subcutaneous. Suitable devices for parenteral administration includeneedle (including microneedle) injectors, needle-free injectors andinfusion techniques.

Capsules (made, for example, from gelatin orhydroxypropylmethylcellulose), blisters and cartridges for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound of the disclosed embodiments, a suitable powder base such aslactose or starch and a performance modifier such as I-leucine,mannitol, or magnesium stearate. The lactose may be anhydrous or in theform of the monohydrate, preferably the latter. Other suitableexcipients include dextran, glucose, maltose, sorbitol, xylitol,fructose, sucrose and trehalose.

The compounds of the disclosed embodiments can also be formulated asDrug-cyclodextrin complexes. Both inclusion and non-inclusion complexesmay be used. As an alternative to direct complexation with the drug, thecyclodextrin may be used as an auxiliary additive, i.e. as a carrier,diluent, or solubiliser. Most commonly used for these purposes arealpha-, beta- and gamma-cyclodextrins, examples of which may be found inInternational Patent Applications Nos. WO 91/11172, WO 94/02518 and WO98/55148.

Since the aspects of the disclosed embodiments may relate to thetreatment of the disease/conditions described herein with a combinationof active ingredients which may be administered separately, they alsorelate to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof Formula I or a salt of such compound and a second compound asdescribed above. The kit comprises means for containing the separatecompositions such as a container, a divided bottle or a divided foilpacket. Typically the kit comprises directions for the administration ofthe separate components.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

Summary of Pharmacokinetic Parameters for Compounds of Formula I

Binding to Opioid Receptors (Binding Assay)

Membrane preparations (from either rodent brain or from cellstransfected with plasmids engineered to express an opioid receptor) arerapidly thawed and diluted in binding buffer (50 mM HEPES, 5 mM MgCl2, 1mM CaCl2, 0.2% BSA, pH 7.4) to a concentration of 0.1 mg/mL. Theradioligand and unlabeled compounds are diluted in binding buffer toachieve the desired final concentration in each well. The assays areperformed in microtiter plates using 40 ul of binding buffer orunlabeled ligand, 10 ul of radioligand (final concentration of(3H)-DAMGO=2 nM), and 50 ul of diluted membranes with three wells pergroup. The plates are then incubated at room temperature for two hours.Unlabeled test compounds are added at one third-log increments with 5log separation between highest and lowest concentrations. The bindingincubation is terminated by the addition of 100 ul cold binding bufferto each well. The glass fiber filter plates are presoaked for 30-45 minwith 0.33% polyethylenimine (PE)I buffer. The PEI solution is removedfrom the filter plate with a vacuum manifold (Millipore) and the filterswashed with 200 ul priming buffer (50 mM HEPES, 0.5% BSA, pH 7.4) perwell. The binding reaction is transferred to the filter plate and washedwith 200 ul washing buffer (50 mM HEPES with 500 mM NaCl and 0.1% BSA,pH 7.4). The plate is dried and the filters removed using a cellharvester and punch assembly (MultiScreen HTS, Millipore) for analysisin a scintillation counter (Beckman Coulter, Fullerton, Calif.). For thecompetitive binding experiments with test compounds, the Ki value wascalculated from the IC50 value by GraphPad Prism, using the equation ofCheng and Prusoff (1973).

Activation of Opioid Receptors (Functional Assay)

Opioid receptors belong to the seven transmembrane superfamily ofheterotrimeric guanine nucleotide-binding protein-(G protein) coupledreceptors, and are linked to the adenylyl cyclase-inhibitory G proteinsGi and Go (Carter and Medzihradsky, 1993). Thus a variety of in vitroassays may be used to establish agonist or antagonist properties ofnovel opioid receptor ligands, including GTP binding (using thenon-hydrolyzable GTP analog GTPγS) and inhibition of cAMP accumulation.

The binding of the nonhydrolyzable GTP analog [³⁵S]GTPγS is often usedto provide a measure of G protein activation by agonists (e.g., Lorenzenet al., 1993; Tian et al., 1994). Because G-protein activation is thefirst biochemical step after opioid receptor activation and is notlimited by downstream effector systems, this assay provides a verydirect measurement of efficacy, and the utility of this assay fordetermining the relative efficacies of mu opioid agonists in vitro hasbeen demonstrated (Traynor and Nahorski 1995; Emmerson et al, 1996). Thecorrelation between the intrinsic activity of a drug in this assay andits efficacy in vivo makes it an appropriate system for measuring therelative efficacies of opioid receptor agonists.

Cell culture. C6(m) rat glioma cells (which lack endogenous opioidreceptors) which had been stably transfected with an opioidreceptor-expressing plasmid (Emmerson et al., 1996) are grown under 5%CO2 in Dulbecco's modified Eagle's medium containing 10% fetal bovineserum. Stock flasks are maintained in the presence of 1 mg/ml Geneticinto select for the presence of the transfected plasmid, which codes forboth the opioid receptor and antibiotic resistance. Cells used forexperiments are split from the stock flasks and grown to confluence inthe absence of Geneticin.

Membrane preparation. Cells are rinsed twice with ice-coldphosphate-buffered saline (0.9% NaCl, 0.61 mM Na2HPO4, 0.38 mM KH2PO4,pH 7.4) and detached from dishes by incubation with lifting buffer (5.6mM glucose, 5 mM KCl, 5 mM HEPES, 137 mM NaCl, 1 mM EGTA, pH 7.4). Thecells are then pelleted by centrifugation, resuspended in ice-cold lysisbuffer (0.2 mM MgSO4, 0.38 mM KH2PO4, 0.61 mM Na2HPO4, pH 7.4) andhomogenized using a glass-glass Dounce homogenizer. Membranes are thenisolated by centrifugation for 20 min at 20,000×g at 4° C. The resultingmembrane pellets are resuspended in 50 mM Tris buffer (pH 7.4) andstored at −80° C. in 1-ml aliquots (approximately 1 mg protein/ml).

Protein determination. Protein concentration in membrane samples isdetermined by the method of Lowry et al. (1951), using bovine serumalbumin as a standard. Samples are solubilized by incubation at roomtemperature in 0.5 N NaOH for 30 min before protein determination.

[35S]GTPγS binding assay. Varying concentrations of ligand arepreincubated with membranes (15 mg membrane protein/tube) for 2 hr at25° C. in binding cocktail [30 mM GDP, 1 mM dithiothreitol, I mM EDTA, 5mM MgCl2, 100 mM NaCl and 47 mM Tris (pH 7.4)] in a 200 ml final assayvolume. Experiments are initiated by the addition of [35S]GTPγS (finalconcentration 40 pM), which is added in a volume of 10 ul H₂O, tominimize any dilution of ligand and other reagents. After 1 min thereaction is terminated by the addition of 2 ml ice-cold washing buffer(50 mM Tris, 5 mM MgCl2, 100 mM NaCl) and the contents of the tubes arerapidly filtered through glass fiber filters (Schleicher & Schuell no.32, Keene, N.H.). The tubes and filters are then rinsed with 2 mlwashing buffer an additional three times. Filters are placed inscintillation vials containing 400 ml ethanol and 4-ml scintillationcocktail for liquid scintillation counting. Nonspecific counts aredetermined from tubes which contained 100 nM unlabeled GTPγS.

Inhibition of cAMP Accumulation. In this assay, cells expressing opioidreceptors (either endogenous or recombinant) are first treated withagents which elevate intracellular cAMP (eg, PGE1 or forskolin) afterwhich test compounds are added to the culture medium and intracellularcAMP is measured by radioimmunoassay or ELISA (Yu et al, 1990, Blake,1997). Specifically, cell monolayers are treated for approximately 30min at 37° C. with culture medium containing 0.5 mMisobutylmethylxanthine. After treatment, the medium is replaced withmedium containing test compound at several different concentrations (eg,10-11 to 10-6 M) and incubated at 37° C. for 5 min. The medium is thenaspirated, and 1 ml of 0.1 N HCl was added; the cells are sonicated andthe monolayers were frozen at −20° C. For determination of the cAMPcontent of each well, the monolayers are thawed, placed on ice,sonicated, and the intracellular cAMP levels measured byradioimmunoassay (Amersham plc, Buckinghamshire, UK). Data obtained fromthe dose-response curves is then analyzed by nonlinear regression (usingGraphPad Prism 2.01 from GraphPad Software, Inc., San Diego, Calif.) tocalculate agonist potency.

In Vivo Measurement of Analgesic Activity and Opioid Side Effects

Determination of analgesic activity is well known to those skilled inthe art. Several methods recognized as characterizing activity arelisted below.

Tail Flick Test.

The method, which detects analgesic activity, follows that described byD'Amour and Smith (1941). Briefly, a mouse's tail is heated by means ofa thermal light source or by immersion in hot water. The latency beforethe animal withdraws its tail is measured (with a maximum time ofexposure to heat of 15 seconds). Opioids are well known to significantlyincrease the latency to tail withdrawal in this assay. In this assay theparent opioid is used as the reference substance (eg, hydrocodone,oxycodone etc), and the dose and pretreatment time for a test agent (eg,a quaternary ammonium derivative) is dependent on the route ofadministration of the test agent (could be oral, subcutaneous,intraperitoneal or intrathecal).

Formalin Test

As described by Shibata et al (1989), 25 ul of 0.5% sterile formalin wasadministered into the right hind paw of a mouse, which elicits acharacteristic, biphasic behavioral response. Each animal was thenreturned to the chamber and pain response was recorded for a period of30 min. The summation of time (in seconds) spent licking and biting theinjected paw during each 5 minute block was measured as an indicator ofpain response. Test agents are administered at various times and dosesprior to formalin injection via oral, subcutaneous, intraperitoneal orintrathecal routes. In this assay, the parent opioid is used as thereference substance (eg, hydrocodone, oxycodone etc), and the dose andpretreatment time for a test agent (eg, a quaternary ammonium derivativeof the parent opioid) to exert analgesic activity is calculated relativeto the parent opioid.

An important side effect of chronic opioid use is constipation. Themethod below describes how a compound of the disclosed embodiments canbe demonstrated to exhibit reduced activity on gastrointestinal motilityrelative to the parent opioid.

Gastrointestinal (GI) Transit.

For measurements of GI transit (Green, 1959), rats were fed by oralgavage with 2 ml of a test meal consisting of 10% vegetable charcoal inwater. Five minutes afterwards animals were euthanized, their smallintestine was removed, its length was measured (from the pyloricsphincter to the ileocecal junction) and the distance traveled by thetest meal was recorded as a percentage of the total length (percentageof GI transit). The effect of test agents (eg, quaternary ammoniumderivative of parent opioid) on GI motility is measured relative to theparent opioid as a reference, with either substance being administeredat various times prior to oral gavage with the charcoal meal.

All publications, including but not limited to, issued patents, patentapplications, and journal articles, cited in this application are eachherein incorporated by reference in their entirety.

Although the invention has been described above with reference to thedisclosed embodiments, those skilled in the art will readily appreciatethat the specific experiments detailed below are only illustrative ofthe invention. It should be understood that various modifications can bemade without departing from the spirit of the invention. Accordingly,the invention is limited only by the claims.

REFERENCES

-   Alt, A et al, (1998) Stimulation of    guanosine-5′-O-(3-[35S]thio)triphosphate binding by endogenous    opioids acting at a cloned mu receptor. J Pharmacol Exp Ther.    286(1):282-8.-   Blake A D, Bot G, Freeman J C, Reisine T. (1997) Differential opioid    agonist regulation of the mouse mu opioid receptor. J Biol Chem.    272(2):782-90. Carter, B. D. and Medzihradsky, F. (1993) Go mediates    the coupling of the mu opioid receptor to adenylyl cyclase in cloned    neural cells and brain. Proc Natl Acad Sci, 90:4062-4066.-   Cheng, Y. and Prusoff, W. H., (1973) Relationship between the    inhibition constant (Ki) and the concentration of inhibitor which    causes 50 percent inhibition (IC50) of an enzymatic reaction.    Biochem. Pharmacol. 22, 3099-3108.-   Emmerson P J, Clark M J, Mansour A, Akil H, Woods J H and    Medzihradsky F (1996) Characterization of opioid agonist efficacy in    a C6 glioma cell line expressing the m opioid receptor. J Pharmacol    Exp Ther 278:1121-1127. Lorenzen A, et al, (1993) Measurement of    guanine nucleotide-binding protein activation by Al adenosine    receptor agonists in bovine brain membranes: Stimulation of    guanosine-59-O-(3-[35S]-triphosphate binding. Mol Pharmacol    44:115-123.-   Lowry O H, Rosebrough N J, Farr A L, Randall R J (1951). Protein    measurement with the Folin phenol reagent. J. Biol. Chem. 193 (1):    265-75.-   Tian W-N, Duzic E, Lanier S M and Deth R C (1994) Determinants of    a2-adrenergic receptor activation of G proteins: Evidence for a    precoupled receptor/G protein state. Mol Pharmacol 45:524-531.-   Traynor J R and Nahorski S R (1995) Modulation by mu-opioid agonists    of guanosine-5′-O-(3-[35S]thio)triphosphate binding to membranes    from human neuroblastoma SH-SY5Y cells. Mol Pharmacol 47:848-854.-   Vallejo R, et al (2011) Pharmacology of opioids in the treatment of    chronic pain syndromes. Pain Physician. 14(4):E343-60.-   Yu V C, Eiger S, Duan D S, Lameh J, Sadee W. (1990) Regulation of    cyclic AMP by the mu-opioid receptor in human neuroblastoma SH-SY5Y    cells. J Neurochem. 55(4):1390-6.

1. A compound of the formula

wherein R¹ is CHR⁴O(C═O)OR⁵, CHR⁴O(C═O)R⁶, CHR⁴O(C═O)NR⁶R⁷,CHR⁴O(C═O)CHR⁸NR⁶R⁷, CHR⁴O(C═O)CHR⁸NH(COCHR⁸NH)_(n)H, CHR⁴R⁹,CHR⁴O(C═O)CR⁵R⁶OR⁷, CHR⁴O(C═O)O(CH₂)_(n)NR⁵R⁶,CHR⁴O(C═O)O(CH₂)_(n)CO₂R⁵, CHR⁴O(C═O)(CH₂)_(n)NR⁵R⁶,CHR⁴O(C═O)(CH₂)_(n)CO₂R⁵,

R² is H; R³ is H, CH₃, or (C═O)CH₃; R⁴ is H or optionally substitutedalkyl; wherein said substituents are independently selected from thegroup OR³ and (C═O)OR⁵; R⁵ is optionally substituted alkyl, cycloalkyl,phenylalkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl; whereinsaid substituents are independently (CH₂)_(n)CO₂alkyl; R⁶ is H or R⁵; R⁷is H or R⁵; R⁸ is H or R⁵; R⁹ is 4-isoxazoyl; wherein each n isindependently an integer from 1-12; and A is an anion selected from thegroup consisting of: Br⁻, Cl⁻, I⁻, R⁷CO₂ ⁻, H₂PO₄ ⁻, NO₃ ⁻, Etodolate,Mefenamate, Urosodeoxycholate and R⁶SO₃.
 2. A compound according toclaim 1 wherein R¹ is CHR⁴O(C═O)OR⁵.
 3. A compound according to claim 1wherein R¹ is CHR⁴O(C═O)R⁶. 4-16. (canceled)
 17. A compound according toclaim 1 wherein R³ is H.
 18. A compound according to claim 1 wherein R³is Methyl.
 19. (canceled)
 20. A compound according to claim 1 wherein R⁴is H.
 21. (canceled)
 22. (canceled)
 23. A compound according to claim 1wherein R⁵ is alkyl selected from methyl, ethyl, isopropyl, n-butyl, orn-pentyl.
 24. (canceled)
 25. A compound according to claim 1 wherein R⁵is cyclohexyl.
 26. (canceled)
 27. A compound according to claim 1wherein R⁶ is H.
 28. A compound according to claim 1 wherein R⁶ ismethyl.
 29. A compound according to claim 1 wherein R⁶ is cyclohexyl.30. A compound according to claim 1 wherein R⁶ is t-butyl.
 31. Acompound according to claim 1 wherein R⁶ is i-propyl.
 32. (canceled) 33.(canceled)
 34. (canceled)
 35. A compound according to claim 1 wherein Ais Br⁻.
 36. A compound according to claim 1 wherein A is Cl⁻.
 37. Acompound according to claim 1 wherein A is I⁻. 38-45. (canceled)
 46. Acomposition according to claim 1 wherein said composition is in tablet,capsule, oral solution, or oral suspension dosage form. 47-52.(canceled)